SYNTHESIS, BIOLOGICAL EVALUATION AND QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP ANALYSIS OF NUCLEAR-SUBSTITUTED PARGYLINES AS COMPETITIVE INHIBITORS OF MAO-A AND MAO-B

A series of nuclear substituted derivatives of pargyline has been prepared and tested (under controlled conditions designed to measure the competitive component of the inhibition) as competitive inhibitors of MAO-A and -B. Adequate correlation of the biological data with the physicochemical constants of substituent groups was obtained only when the m- and p-substituted derivatives were considered separately. Due to the narrow range of activity displayed by the p-substituted derivates when inhibiting MAO-B, meaningful correlations were not found. However, the inhibition of MAO-B by the m-substituted derivatives required the inclusion of the Verloop L parameter for adequate correlation, suggesting that the inhibitor binding site of MAO-B is present within a cavity of more limited lateral dimensions than that present on the MAO-A surface. Inhibition of both MAO-A and -B demonstrated a parabolic relationship between inhibitory activity and pi. Whereas this parabolic relationship showed a maximal value for inhibition of MAO-A (mean pi(o) = 0.86), inhibition of MAO-B demonstrated a minimal value of pi (pi(min) = -0.5) i.e. the optimal value of pi for inhibition of MAO-B has not been achieved for this series of compounds but such would be greater than that demonstrated for MAO-A. The Hammett sigma-function was important or significant only in the inhibition of MAO-A by the p-substituted derivatives.